Bioadhesive Compositions of Local Anaesthetics

Abstract

The present invention relates to a gelling bioadhesive pharmaceutical composition comprising one or more local anaesthetics in base form and which is suitable for topical administration. The compositions have anisotropic organic phase behaviour that admits swelling at administration site with excess water.

1 . An aqueous stabilized pharmaceutical bioadhesive gelling composition comprising;
 (a) an anaesthetically effective amount of one or more local anaesthetics;   (b) a monoglyceride or a diglyceride, or mixtures thereof of a long chain fatty acid in an amount of between 15 to 70% by weight; and   (c) a free long chain saturated or unsaturated fatty acid in an amount of between 5 to 60% by weight, wherein the composition has an anisotropic organic phase behaviour that admits swelling at administration site with excess water.   
     
     
         2 . The pharmaceutical composition according to  claim 1  further comprising;
 (d) one or more solubilizer in an amount of between 0 to 30% by weight, preferably between 5 to 25% by weight and most preferably between 5 to 15% by weight. 
 
     
     
         3 . The pharmaceutical composition according to  claim 1  wherein the one or more local anaesthetics are present in an amount of between 0.1 to 20% by weight, preferably in an amount of between 0.5 to 12% by weight, most preferably in an amount of between 2 to 10% by weight. 
     
     
         4 . The pharmaceutical composition according to  claim 1  wherein the one or more local anaesthetic is a local anaesthetic of the amide type, ATC code N01BB. 
     
     
         5 . The pharmaceutical composition according to  claim 4  wherein the local anaesthetic of the amide type is selected from lidocaine, prilocaine, mepivacaine, ropivacaine, bupivacaine, and levobupivacaine. 
     
     
         6 . The pharmaceutical composition according to  claim 1  wherein the one or more local anaesthetic is a local anaesthetic of the ester type, ATC code N01BA. 
     
     
         7 . The pharmaceutical composition according to  claim 6  wherein the local anaesthetic of the ester type is selected from the group consisting of benzocaine, tetracaine, and chloroprocaine. 
     
     
         8 . The pharmaceutical composition according to  claim 1  wherein the one or more local anaesthetic is a long acting local anaesthetic. 
     
     
         9 . The pharmaceutical composition according to  claim 8  wherein the long acting local anaesthetic is selected from the group consisting of ropivacaine, bupivacaine, and levobupivacaine, preferably, the local anaesthetic is ropivaciane. 
     
     
         10 . The pharmaceutical composition according to  claim 1  wherein the one or more local anaesthetic is a short acting local anaesthetic. 
     
     
         11 . The pharmaceutical composition according to  claim 10  wherein the short acting local anaesthetic is selected from the group consisting of lidocaine, prilocaine, and mepivacaine. 
     
     
         12 . The pharmaceutical composition according to  claim 1  wherein the total amount of monoglycerides or diglyceride and free fatty acids together is more than 50% by weight in the composition, preferably between 50 to 75% by weight. 
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein the content of water is less than 30% by weight, preferably, between 5 to 20% by weight. 
     
     
         14 . The pharmaceutical composition according to  claim 1 , wherein the monoglycerides and/or diglyceride are present in an amount of 20 to 50% by weight. 
     
     
         15 . The pharmaceutical composition according to  claim 1  wherein monoglyceride is glycerol monooleate 
     
     
         16 . The pharmaceutical composition according to  claim 1  wherein the one or more fatty acids are present in an amount of between 15 to 70% by weight, preferably in an amount of between 25 to 50% by weight. 
     
     
         17 . The pharmaceutical composition according to  claim 1 , wherein the fatty acid is selected among long-chain unsaturated fatty acids, preferably single unsaturated fatty acids, most preferably the fatty acids are selected among oleic acid and ricinoleic acid. 
     
     
         18 . The pharmaceutical composition according to  claim 1 , wherein the fatty acid is selected among long-chain saturated fatty acids, most preferably the fatty acids are selected among palmitic acid and stearic acid. 
     
     
         19 . The pharmaceutical composition according to  claim 2  wherein the solubilizer is selected from the group consisting of non-ionic surfactants, preferably polysorbates or sorbitan fatty acid esters, glycerol formal, a polyoxyethylated castor oil (such as Cremophor EL). 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the solubilizer is of the polysorbate type or a polyoxyethylated castor oil. 
     
     
         21 . The pharmaceutical composition according to  claim 1  wherein the final pH-value for the composition is higher or equal to the pKa of the local anaesthetic minus 1.0, preferably the final pH-value for the composition is higher or equal to the pKa of the local anaesthetic minus 0.5, even more preferably the final pH-value for the composition is higher or equal to the pKa of the local anaesthetic. 
     
     
         22 . The pharmaceutical composition according to  claim 1  comprising;
 ropivacaine in an amount of between 3 to 10% by weight; 
 glycerol monooleate in an amount of between 40 to 70% by weight; 
 oleic acid or ricinoleic acid in an amount of between 15 to 30% by weight; and 
 a solubilizer in an amount of between 10 to 20% by weight. 
 
     
     
         23 . A composition according to  claim 22 , comprising water in an amount between 10 and 20% by weight that is essentially semi-solid or solid at body temperature. 
     
     
         24 . A method of preparing a gelling bioadhesive pharmaceutical composition
 capable of exerting a long term anaesthetic effect in an aqueous environment comprising the consecutive steps of:   (a) providing a mixture of a monoglyceride of long-chain unsaturated fatty acid, a free long-chain fatty acid and a solubilizer for a local anesthetic;   (b) adding a local anaesthetic to the mixture of step (a);   (c) adding a water at a basic pH to the mixture of step (b); and   (d) obtaining a gelling composition with an isotropic organic phase behaviour that admits swelling at an administration site with excess water.   
     
     
         25 . A method of manufacturing a stabilized local anaesthetic product with such a low level of viable microorganisms that the product is suitable for topical administration to an internal body site, comprising the steps of:
 a) providing a composition of a local anaesthetic in a concentration of between 1 to 10% by weight and solubilized with at least 5% of a solubilizer, the composition further comprising at least 50% by weight of a monoglyceride or a diglyceride, or mixtures thereof of together with a long chain free fatty acid;   b) preparing a sealed container comprising the composition;   c) subjecting the container with the composition to heat sterilization (autoclavation) at less than 120° C. for about 10 minutes and;   d) obtaining a local anaesthetic product with maintained gelling characteristics and with so low level of viable microorganisms that the product is suitable for topical administration to an internal body site.   
     
     
         26 . A method according to  claim 24 , wherein the monoglycerides and the fatty acid together is included to more than 50% by weight, preferably between 50 to 75% by weight, in the resulting composition; and wherein the water content is between 5 to 20% by weight in the resulting composition. 
     
     
         27 . A method according to  claim 24 , wherein the monoglycerides is glycerol monooleate and the fatty acid is oleic acid. 
     
     
         28 . A method according to  claim 24 , wherein the solubilizer is of a polysorbate, a sorbitan fatty acid ester or a polyoxyethylated castor oil and the local anaesthetic is ropivacaine.